Otosclerosis has been traditionally managed with hearing aids and surgery, but a recent discovery may result in development of a biochemical treatment

Thomas Morrow, MD

The most common cause of hearing loss, which affects about 28 million Americans, is otosclerosis, which was first suspected to be a disease process in 1889 when Adam Politzer, MD, a Viennese clinician, observed during an autopsy of a patient who had no middle ear pathology but had new bone formation anterior to the oval window.

Four years later he had collected an additional eight cases and presented his findings in Washington D.C. at the Pan-American Medical Congress. His case studies describing the ossification of the middle ear became the basis of the theory of otosclerosis.

Otosclerosis derives its name from two Greek words, oto, meaning ear, and sclera, meaning hard. It describes the abnormal growth of bony tissue involving the small bones of the middle ear.

For sound to be transmitted from the ear drum to the inner ear, the stapes must be able to vibrate. The sound vibrations from the ear drum travel along the three small bones of the middle ear, the malleus (hammer), incus (anvil) and stapes (stirrup). The stapes is connected to a thin membrane, the oval window, which separates the air-filled outer ear from the fluid-filled inner ear.

The amplifier

When the stapes vibrates, it moves the inner ear fluids that in turn stimulate the hair cells, which then stimulate the auditory nerve directly. Together these three bones and the eardrum act as amplifier and transducer, changing sound into mechanical energy.

About 10 percent of Caucasians are affected by otosclerosis, but it is very rare in Asians, American Indians, and blacks. The slowly progressive hearing loss starts between ages 15 and 45. Otosclerosis is more common in women than in men, and it is, for some unknown reason, particularly troublesome for pregnant women, who can develop rapidly worsening hearing loss.

Other symptoms include dizziness, balance problems, and tinnitus. The hearing loss is bilateral in about 80 percent of patients. In most, but not all cases, the nerves of hearing are not affected. This is why a patient who undergoes a hearing test that transmits sound directly to the skull bones will pass, but the same patient will fail an audiogram, which is conducted using traditional earphones.

Current treatment

Treatment varies based upon the degree of hearing loss. Hearing aid amplification is the mainstay of therapy, as no medication has been proven to be effective in treating otosclerosis.

In many cases, patients progress to the point where the only viable therapy is stapedectomy, in which the diseased stapes are surgically removed.

During this procedure, first performed in the mid-1950s, the stapes is replaced with one of a variety of prosthetic devices. The prosthesis restores the movement needed to stimulate the fluid in the inner ear.

This procedure is performed on an outpatient basis and is accompanied by a few temporary side effects such as dizziness and taste disturbances. Because the chorda tympani nerve, a small nerve involved with taste, runs through the ear canal, taste sensation may change for a period following surgery because of minor trauma.

With the patient under local or general anesthesia, the surgery is performed through the ear canal with no visible outer incisions. Under direct observation using an operating microscope, the ear drum is cut to expose the middle ear. The upper portion of the stapes is removed and in most cases a hole is drilled into the footplate — the connection between the stapes and the oval window. Occasionally, the entire footplate must be removed because of extensive disease. Finally the prosthesis is inserted.

Gene discovery

About 60 percent of otosclerosis cases have a genetic component. In fact, if one parent has this disorder, the children have about a 25 percent chance of developing the disease. If both parents suffer from otosclerosis, the probability rises to 50 percent.

At the European Society of Human Genetics in June, Belgian researchers reported that they have identified a gene that appears to be the major culprit — the TGBF1 gene. This gene is involved in the embryonic development of the ear and was thought to be involved in the development of otosclerosis for some time, but no proof was available until now.

Researchers conducted an exact nucleotide sequence analysis of the TGBF1 gene in a group of people with otosclerosis. They identified a common specific variant single nucleotide change, also called a single nucleotide polymorphism (SNP), in the TGBF1 gene. A second analysis, conducted on French patients, also pointed to this gene. A second variant of the gene appears to protect against the disease, bolstering evidence for TGBF1 involvement.

The TGBF1 gene codes for a growth factor. A single nucleotide change in the TGBF1 gene, which in turn causes a single amino acid change in the growth factor, appears to cause abnormal growth of the small ossicles in the ear. Although this finding does not change the current therapy for patients suffering from otosclerosis, it demonstrates the rapid progress being made in human genetics.

Why is this finding important?

As researchers delve deeper into the genetic causes of diseases, they often find a single protein, and hence gene, that is responsible. A single amino acid in a critical position can change the shape of an entire protein, in turn affecting the process this protein controls. It can increase, decrease, or destroy the action of the protein.

As specific proteins are discovered, the logical step is to use this knowledge to develop a medical therapy that will in some way increase, decrease, or stop the activity of the changed protein. A number of therapeutic options are available and range from monoclonal antibodies to receptor antagonists. Research is almost certain to follow if the disease is common enough or severe enough to support a therapy economically.

For those people affected by otosclerosis today, this discovery is unlikely to produce much of a change in their immediate future, but their children are almost certain to benefit as today's discovery inevitably leads to Tomorrow's Medicine!

Thomas Morrow, MD, is the immediate past president of the National Association of Managed Care Physicians. He has 21 years of managed care experience at the payer or health plan level.
The author is a director in the value-based health department at Genentech Inc. During the last three years, before taking the Genentech position, he received honoraria or other financial benefits from: Amgen, Amylin Pharmaceuticals, AstraZeneca, Biogen Idec, Centocor, Galderma, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Novo Nordisk, Pfizer, Procter & Gamble, Q-Med, Sanofi-Aventis, Teva Pharmaceuticals Industries, UCB, and Wyeth. The views expressed in Tomorrow's Medicine are the author's alone.

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